A substantial body of data indicates that neuroendocrine factors play a role in the expression of autoimmune diseases such as rheumatoid arthritis (RA). A detailed understanding of these factors should provide important insights into the prevention and therapy of these diseases. We are conducting studies addressing the role of the hypothalamic-pituitary-adrenal- (HPA) and - gonadal-axes in RA. We have investigated circadian secretion of ACTH, cortisol and interleukin-6 (IL-6) in RA patients compared to age-, gender-, and race-matched controls. Overall, ACTH and cortisol secretion were similar in patients and controls, although RA patients exhibited earlier mornings secretion patterns. However, RA patients secreted substantially higher levels of IL-6. Lead-lag correlation analysis indicated that cortisol secretion was linked to IL-6, with IL-6 leading cortisol by about 1 hour. Moreover, a negative correlation was noted at about 5 hours with cortisol leading IL-6, indicating that IL-6 and cortisol are linked in a bidirectional feedback loop. Our data support the view that HPA axis responses in RA patients are "inappropriately normal". RA patients show a relative insensitivity to IL-6-stimulated HPA axis activation (Crofford L et al. Arthritis Rheum. 38, S289, 1995; Crofford L et al., submitted for publication). We are conducting follow-up studies in new-onset arthritis patients. Although these studies are not complete, our data continue to suggest that RA patients, even with new onset disease, have abnormalities in adrenocortical function. Since deficient HPA axis function probably has pronounced effects on immune function, we have also been investigating this hypothesis. In particular, we have been exploring the effects of cortisol and other stress hormones on TH1/TH2 cytokine balance. Using an in vitro whole blood assay, we have assessed the effects of corticosteroids, epinephrine and norepinephrine on LPS- induced secretion of IL-12 p70, a proinflammatory TH1 cytokine, and IL-10, an antiinflammatory cytokine. We have demonstrated that all 3 mediators have pronounced inhibitory effects on IL-12, but not IL-10, secretion. In fact, both epinephrine and norepinephrine strongly stimulate IL-10 secretion. These data clearly indicate that stress hormones may regulate TH1/TH2 cytokine balance (Elenkov I et al., Proc. Amer. Assoc. Phys., 1996, in press). The data suggest an important role for the stress response system in regulating immune function in diverse clinical settings. Our laboratory has also been interested in characterizing TH1/TH2 cytokine gene expression in RA and other forms of new-onset synovitis. In a study of more than 200 synovial specimens from patients with new onset disease, we have demonstrated that cytokine profiles are skewed toward proinflammatory macrophage-derived and TH1 type cytokines, such as TNF-alpha, IL-1 beta, IL-12, IL-15 and interferon-gamma. IL-10, not IL-4 or IL-13, appears to be the major antiinflammatory cytokine mRNA (Kotake S. Et al., Arthritis Rheum. 38, S354, 1995; Kotake s et al., submitted for publication). These data provide new insights into the pathogenesis of RA and related forms of arthritis.